With aging, functional or structural declines are seen in tissues and organs. Many different hypotheses have been proposed to understand aging at the tissue or individual level. Genes involved in aging phenotypes and/or individual longevity have been reported, yet the exact in vivo mechanism(s) underlying the progression of aging-associated changes at the tissue level is not sufficiently understood.
Intrinsic DNA damage that may be caused by errors in DNA replication, reactive oxygen species, telomere end problems, chromosomal abnormalities or such is known to accumulate in tissue-constituting cells, and they relate to tissue aging. Typical aging phenotypes such as graying and hair loss are known to be facilitated by not only intrinsic genome instability seen in premature aging syndromes, but also extrinsic genome instability caused by environmental factors such as radiation exposure.
Tissue atrophy due to genome instability has been explained with cellular senescence or cell death. However, typical senescent cells are not readily induced in skin tissues simply with genomic instability, but rather appear in papilloma and melanocytic nevi in the skin, and they are thought to relate to inhibition of carcinogenesis. Today, aging-associated changes in tissue stem cells (stem cell aging) are seen as one of the features of aging; however, the fate of aged tissue stem cells, influence of DNA damage on the fate, and also the role in the aging process of tissues and organs have not yet been made clear.
Hair follicle stem cells localize in the bulge region inside hair follicles, and they are responsible for hair regrowth at each hair cycle (Patent Document 1; Non-patent Document 1). It has been reported that mouse HFSCs generally do not display apparent decline, but in fact, the telogen phase becomes longer with age, and changes are seen in the cytokine signals in HFSCs, and their colony-forming ability is also reduced. On the other hand, mammals that live longer lose their hair and HFs with age.
Hair growth is generally classified into the growth phase (anagen), regressing phase (catagen) and resting phase (telogen) (Non-patent Document 2). In the case of human hair, after the growth phase continues for two to seven years, it goes through the regressing phase and resting phase, and then hair falls out.
The primary function of hair is protection from trauma or direct sunlight, prevention of loss of body temperature and such; and hair follicles also carry the role of reservoir for skin stem cells. Further, hair is also important in terms of mediating social communication, and decrease of hair volume may bring about reduction of quality of life in people.
Among alopecia, there are male pattern alopecia, female pattern alopecia, seborrheic alopecia, senile alopecia, alopecia areata, drug alopecia, scarring alopecia, postpartum alopecia occurring after childbirth, and such. Medicament alopecia and scarring alopecia include those iatrogenically induced by the side effects of cancer treatments with anticancer agents and X-ray radiation, respectively. However, ways of dealing with the alopecia have not been established as of now.
The major hair growing agents/hair tonics currently approved as pharmaceuticals include minoxidil and finasteride. Minoxidil is a pharmaceutical originally developed as an oral hypertensive drug that works mainly on blood vessel dilation. In patients receiving treatment of the hypertensive drug, vasodilation and hypertrichosis such as facilitation of hair root regeneration were observed; and thus, the pharmaceutical was newly developed as an external hair growth agent for medical use. Minoxidil promotes the production of cell growth factors (VEGF and such) from dermal papilla cells, and induces vasodilation by activating vascular smooth muscle ATP-sensitive K channels. This is known to transfer hair follicles from the resting phase to the initial growth phase, and has the effect of extending the growth phase and making the hair grow thick.
DHT (dihydrotestosterone) has the effect of inhibiting hair growth mainly in the frontal region and parietal region. Finasteride works by inhibiting type II 5-α reductase which is an enzyme that converts testosterone to DHT, and suppressing DHT synthesis. The pharmaceutical was developed by applying the drug for treatment of prostatic hypertrophy which is caused by male hormone as a therapeutic agent for androgenetic alopecia (AGA).
Despite that these pharmaceuticals are currently on the market, more effective medicaments are in demand for countermeasures against hair loss. Similarly, more effective medicaments are in demand for countermeasures against graying.